Investigators at Children’s Hospital Los Angeles Identify Pathway
that Causes Immune Cells to Support Cancer, Instead of Killing It

September 26, 2017 04:00 PM Eastern Daylight Time

LOS ANGELES--(BUSINESS WIRE)--Investigators at the Children’s Center for Cancer and Blood Diseases at
Children’s Hospital Los Angeles have identified new findings about an
immune cell – called a tumor-associated macrophage – that promotes
cancer instead of fighting it. They have identified the molecular
pathway, known as STAT3, as the mechanism the immune cell uses to foster
neuroblastoma, a pediatric cancer, and have demonstrated use of a
clinically available agent, ruxolitinib, to block the pathway. Results
of the study were published in the journal Oncotarget on
September 20.

Neuroblastoma is the second most common solid tumor effecting children.
Individuals with high-risk disease have a mortality rate of
approximately 50 percent. Certain conditions are associated with
high-risk disease. High levels of some chemicals involved with
inflammation and the presence of an immune cell called a
tumor-associated macrophage (TAM) are associated with high-risk disease
and lower survival rates. Macrophages are a type of immune cell that
typically function to battle disease, not encourage it.

“The macrophages are essentially co-opted by the tumor cells to help
them grow,” said Shahab Asgharzadeh, MD, director of the Basic and
Translational Neuroblastoma program at CHLA and lead investigator of the
study. “We’re trying to find out more about the mechanisms that enable
TAMs to help cancer grow so that we can target the pathways they use and
block their pro-tumor effect.”

The team wanted to find out whether effective therapeutic approaches for
children with neuroblastoma could be based on targeting
inflammation-associated biologic pathways in the area surrounding the
tumor, called the tumor microenvironment. Using a mouse model to examine
the activity of TAMs within the tumor microenvironment, the research
team observed the “recruitment and polarization” of TAMs which enhance
the ability of neuroblastoma to spread and grow. They found that TAMs
exhibit a dual role – not only nourishing the neuroblastoma but also
effectively helping them to evade the “good immune cells” seeking to
kill the tumor cells.

To study the effect of TAMs on neuroblastoma cell growth and
proliferation, the investigators co-cultured both mouse and human
neuroblastoma cells with TAMs and found a significant increase compared
to tumor cells without TAMs.

In an effort to find out what the TAMs were secreting that caused
stimulation of tumor cells, the investigators targeted IL-6, an immune
substance known to cause proliferation of certain types of cancer. Using
a mouse model that lacked IL-6, they still observed increased tumor
growth. In these experiments, they noted activation of the STAT3
cell-signaling pathway – known to promote tumor growth preceding an
increase of MYC – a gene that drives many types of cancer.

These findings led them to target the STAT3 pathway. Using a clinically
available drug, ruxolitinib, known to block the STAT3 pathway, the
investigators co-cultured both human and mouse TAMs and neuroblastoma
cells. They observed that the immune cells no longer supported tumor
growth.

“Targeting STAT3 may be a promising approach to block interactions
between tumor cells and the ‘traitorous’ immune cells, and a way to
improve outcomes for children with high-risk neuroblastoma,” said
Asgharzadeh, who is also a professor of pediatrics with the Keck School
of Medicine of the University of Southern California.

According to Asgharzadeh, the next step is to combine agents that block
the STAT3 pathway with drugs that have been effective in treating
neuroblastoma.

Other contributors to the paper include Michael D. Hadjidaniel,
Sakunthala Muthugounder, Long T. Hung, Michael A. Sheard, Soheila
Shirinbak, Randall Y. Chan, Rie Nakata, Lucia Borriello, Jemily Malvar,
Rebekah J. Kennedy, Hiroshi Iwakura, Takashi Akamizu, Richard Sposto,
Hiroyuki Shimada, and Yves A. DeClerck, all of Children’s Hospital Los
Angeles, along with Hiroshi Iwakura and Takashi Akamizu of the First
Department of Medicine, Wakayama Medical University in Japan.
Asgharzadeh, Sposto, Simada and DeClerck are also faculty members of the
Keck School of Medicine of USC. The research was supported by grants
from the Department of Defense (CDMRP10669916), (W81XWH-12-1-0571), the
T.J. Martell Foundation, the Norris Foundation, the Nautica Malibu
Triathlon and the National Institutes of Health U54 (5U54CA163117).

About Children's Hospital Los Angeles

Children's Hospital Los Angeles has been ranked the top children’s
hospital in California and sixth in the nation for clinical excellence
with its selection to the prestigious U.S. News & World Report Honor
Roll. CHLA is home to The Saban Research Institute, one of the largest
and most productive pediatric research facilities in the United States.
Children’s Hospital is also one of America's premier teaching hospitals
through its affiliation with the Keck School of Medicine of the
University of Southern California since 1932. For more information,
visit CHLA.org.